1. Field
This invention relates to the topical application of estrogen and estrogen analogs and other estrogen receptor modulators in the treatment of primary or secondary dry eye syndrome (also known as keratoconjunctivitis sicca (KCS)) and, in certain embodiments, to the preparation and application of 17-β-estradiol and its derivatives in lipid, liposomes, polymers, or aqueous or non-aqueous vehicles for the topical treatment of the ocular surface tissues particularly as time-release or micro-dose formulations. This invention may also be useful in treating other conditions where KCS may occur, such as post-operative refractive surgery and corneal transplant patients.
2. Related Art
The high incidence of keratoconjunctivitis sicca in the population of postmenopausal women is attended by symptoms ranging from mild foreign body sensation to frank pain and visual loss due to ocular surface abnormalities.
It is known that tear film quality depends on fine regulatory mechanisms affected by neuronal and hormonal influences. Indeed, receptors for androgens, estrogens, progesterone and prolactin have been identified in several ocular tissues in the rat, rabbit and in humans. These hormones influence the immune system, the morphology and secretory functions of lacrimal glands, the morphology and function of the conjunctiva, and the functioning of Meibomian glands. The influence of hormone replacement therapy in menopausal women remains unclear, as some authors support the idea that hormones improve the quality and the volume of tear film, whereas others have argued that they increase the risk of dry eye. Finally, knowledge of the interactions between the hormones that influence the function of the lacrimal gland is an essential element for the understanding of the regulation of lacrimal gland function. Additional data suggest that optimal bioavailable androgen levels are essential for normal lacrimal gland function and that prolactin and estrogens also play important roles in providing a hormonal milieu that contributes to normal lacrimal gland function (Oprea, L., Tiberghien, A., Creuzot-Garcher, C., Baudouin, C., Hormonal Regulatory Influence in Tear Film, J. Fr. Ophtalmol., October 27(8):93341 (2004)).
The standard treatment with artificial lubricants provides temporary symptomatic relief in most cases, but does not address the cause of the dry eyes. While there has been described treatment of post menopausal females with dry eye syndrome using oral Premarin therapy, the oral or parenteral administration of estrogen can frequently produce side effects such as vaginal bleeding, breast tenderness and other undesired effects and the therapeutic effects derived from oral therapy do not justify the risk. Further, such oral, dermal (e.g., application to the skin of the outer eyelid) or parenteral administration implicates the entire body structure in an indeterminate effort to secure an effect in a localized area (the eye), in the absence of any data relating the level of estrogen introduced into the blood stream to the level, if any, resulting in the tear fluid (it is known generally, that estrogen concentrations in the eye to be in the range of about 10% of serum levels). Conservative medicine would indicate the desirability of limiting the specific effect of the hormone to the target site if possible.
As the data in U.S. Pat. No. 6,096,733 demonstrates, the effective concentration of 17-β-estradiol in solution can be as low as 0.1% and continue to be effective regardless of the presence or absence of concomitant oral estrogen therapy in post-menopausal women. This lower dose range is especially useful in providing eye drops that will contain a concentration of 17-β-estradiol that is low enough to be both safe and effective (the medical aspect) yet has the potential to be approved by the FDA for use in non-prescription (OTC) based formulations (the commercial aspect). However, the low dose of 0.1% was applied three or four times per day in U.S. Pat. No. 6,096,733. Thus, U.S. Pat. No. 6,096,733, while providing a low dose formulation, did not provide examples of a time release or micro-dose formulation that could be used only at lower frequency.
In addition, the low dose formulation in the U.S. Pat. No. 6,096,733 exhibits side effect due to systemic effects of the 17-β-estradiol administered topically. When a lower does (0.05% 17-β-estradiol) was tested in a Phase IIb trial, it showed lower efficacy than the 0.1% dose for all but one of the signs and symptoms recorded for the trial. Thus, there is a need for formulations that can provide an efficacious dose without the systemic side effects, preferably with a lower frequency of dosing.